Articles and methods of treating vascular conditions

ABSTRACT

The present invention relates to articles and methods of treating vascular conditions with a thixotropic, turbid, bioactive agent-containing gel material capable of being essentially removed from an implantation site upon re-establishment of fluid flow at the implantation site.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/466,459, filed Aug. 22, 2014, which is a divisional of U.S.application Ser. No. 12/404,083, filed Mar. 13, 2009, both of which areherein incorporated by reference in their entireties for all purposes.

FIELD OF THE INVENTION

The present invention relates to articles and methods of vascular-basedtherapies to treat a variety of vascular conditions.

BACKGROUND OF THE INVENTION

Vascular conditions arise from a variety of causes, and in some cases,necessitate surgical or endovascular intervention. Trauma to thevascular system may also necessitate surgical intervention to treat thetraumatized anatomy. The long-term implantation of vascular prosthesesincluding vascular grafts, stent-grafts, and stents, and the applicationof treatment modalities, including balloon angioplasty are oftenundertaken to treat vascular conditions including vascular disease andvascular trauma.

Consequences of surgical intervention have been observed followingimplantation of vascular prostheses including vascular grafts,stent-grafts, stents, and other prostheses, particularly when ananastomosis is formed. The consequences of surgical interventioninclude, but are not limited to, inflammation, intimal hyperplasia,stenosis, and restenosis of the treated blood vessel near the formedanastomosis. Inflammation is a physiological response by a mammalianbody to surgery, injury, irritation, or infection. An inflammatoryresponse involves complex biological activities at chemical, cellular,tissue, and organ levels. Generally, an inflammatory response is aprotective attempt to remove an injurious stimulus, as well as toinitiate a healing process for the diseased or traumatized tissue.Intimal hyperplasia is a pathological condition in which an overabundantinflammatory response is initiated involving stimulation, migration, andproliferation of numerous cell types. Stenosis and restenosis areconstrictions of the blood vessel lumen and may be caused by mechanismsincluding, but not limited to, compliance mismatch between the nativevessel and the implanted vascular prosthesis, host tissue response to animplanted material, prior disease states, and infection. Stenosis andrestenosis can progress to a point where additional surgicalintervention is required to enlarge the blood vessel lumen diameter ofthe blood vessel or the implanted vascular prosthesis to establish aless restrictive conduit for blood flow.

Additional vascular conditions that may require surgical or endovascularintervention include, but are not limited to, vascular injury, vascularprophylactic intervention, vascular disease, phlebitis, intimalhyperplasia, vulnerable plaques, carotid plaques, coronary plaque,vascular plaque, aneurismal disease, vascular dissections,atherosclerotic plaques, atherosclerotic lesions, vascular infection,and vascular sepsis.

One approach to treatment of these vascular conditions involves localdelivery of a suitable pharmaceutical or biologically active agent in aliquid vehicle within luminal spaces of a blood vessel at or near thesite of the vascular condition. The liquid vehicle containing thepharmaceutical or biologically active agent is contacted with tissues ofthe luminal space at a vascular treatment site for a determined lengthof time (dwell time). However, this approach often requires extensivedwell times at the vascular treatment site to ensure adequate deliveryand retention of the bioactive agent at the vascular treatment site totreat the vascular condition. Even with extensive dwell times, thedelivery and retention of the bioactive agent at the vascular treatmentsite using this approach may be insufficient to treat the vascularcondition.

Another therapeutic approach is the implantation of vascular prostheseshaving a pharmaceutical-containing coating to deliver a pharmaceuticalto a lumen of a blood vessel or other vascular conduit. Examples ofvascular prostheses having a pharmaceutical-containing coating include,but are not limited to, stents, stent grafts, grafts, and angioplastyballoons. Other examples of vascular prostheses having apharmaceutical-containing coating are drug eluting stents and drugeluting stent grafts (DESs). DESs are used in the treatment of coronaryartery disease and peripheral artery disease. A high degree of physicianskill is often required to implant DESs without damaging or traumatizingsurrounding vascular tissue. The treatment of a vascular condition bythe implantation of DESs may require long term implantation of thevascular prosthesis. The long term implantation of the vascularprosthesis may also result in mechanical trauma to the vasculartreatment site due to a nonlubricious nature of thepharmaceutical-containing coating. The long term implantation of thevascular prosthesis may also result in an unwanted tissue reaction atthe vascular treatment site due to the components of the vascularprosthesis and/or the pharmaceutical-containing coating. Therefore it isdesirable to have an improved method for treating vascular conditionsthat requires minimal physician skill to perform. It is desirable tohave an improved method for treating vascular conditions that avoidslong term implants.

Drug eluting balloons (DEBs) are additional examples of vascularprostheses having a pharmaceutical-containing coating. The literaturediscloses the use of DEBs for the treatment of coronary artery diseaseand peripheral artery disease (see e.g., U.S. Pat. No. 5,102,402, issuedto Dror et al.). Dror et al. disclose placing a DEBs in a blood vessellumen to treat the vessel wall, inflating the balloon, and contactingthe balloon surface with the luminal vessel wall to deliver apharmaceutical into the blood vessel wall. Another example of treatmentusing DEBs involves an angioplasty balloon having microneedles (seee.g., U.S. Pat. Nos. 5,171,217; 5,538,504; and 6,860,867). DEBs oftenrequire a high degree of physician skill to implement. The implantationof the DEBs may also result in mechanical trauma to the vasculartreatment site due to the components of the DEBs and/or thepharmaceutical-containing coating. It is desirable to have improvedmethods for treating and preventing vascular conditions that are simpleand easy to implement. It is also desirable to have methods for treatingand preventing vascular conditions that avoid mechanical trauma to thevascular treatment site and are compatible with the delivery of a widevariety of pharmaceuticals.

In addition to delivering drugs to blood vessels from stents,stent-grafts, grafts, and other prostheses, intraluminal drug deliverymethods include methods that chemically “pave” luminal surfaces of ablood vessel (see e.g., U.S. Pat. Nos. 5,213,580; 5,674,287; 5,749,922;and 5,800,538). These “paving” methods involve fixation, polymerization,and bonding of a drug delivery system to the lumen of a blood vessel.Degradation of such delivery systems ranges from days to weeks. Themethods can be challenging as they involve chemical reactions with theblood vessel lumen. These chemical reactions may induce trauma to thevascular treatment site. It is desirable to have improved methods fortreating and preventing vascular conditions which avoid “paving” of theluminal surfaces of the blood vessel.

Methods of delivering drugs to perivascular locations are described.U.S. Pat. No. 6,726,923, issued to Iyer, and U.S. Pat. No. 5,527,532,issued to Edelman, disclose perivascular drug eluting wraps and matricesapplied to adventitial surfaces of a blood vessel to treat vascularinflammation.

U.S. Pat. No. 5,893,839, issued to Johnson, discloses a method oftreating restenosis involving the delivery of a biologically activesubstance percutaneously.

U.S. Pat. No. 6,730,313, issued to Helm us et al., discloses a methodfor treating intimal hyperplasia involving contacting an exteriorsurface of a blood vessel with a “flowable” drug delivery vehicle.

These methods usually require complex procedural techniques, oftenimplemented through invasive surgical techniques. In addition, thesemethods may require long term implantation of a vascular prosthesis,drug eluting wraps, matrices, and flowable drug delivery vehicles. Longterm implantation of the vascular prosthesis, drug eluting wraps,matrices, and flowable drug delivery vehicles may also result in anunwanted tissue reaction at the vascular treatment site due to thenature of their components. It is desirable to have improved methods fortreating and preventing vascular conditions that allow delivery of awide variety of pharmaceuticals and biologics to diseased or traumatizedvascular tissue without the need for long term implants, that are easilyimplemented, and that are applied through surgical and endovasculartechniques.

Li et al. (U.S. Patent Application Publication 2002/0019369) disclose aninjectable cyclodextrin polymer-based composition made fromcyclodextrin, polyethylene glycol, and a pharmacologically effectiveamount of at least one drug. Li et al. further disclose theircomposition can be used subcutaneously, intramuscularly, intradermally,or intracranially. However, Li et al. do not teach their composition canbe injected into the vasculature or into flowing blood.

As is disclosed to the literature, compositions made of cyclodextrin andpolyethylene glycol form inclusion complexes. The inclusion complexeshave the form of hydrogels, turbid solutions, and precipitates (Li, JBiomed Mater Res, 65A, 196, 2003; Harada, Macromolecules, 26, 5698,1993; Harada, Macromolecules, 23, 2821, 1990).

Indeed, as indicated by the literature, injection of particles in theform of hydrogel materials, turbid solutions, and precipitates into thevasculature or into flowing blood can have adverse consequences,including decreased drug effectiveness, phlebitis, embolism, andblockage of capillaries (Nemec, Am J Heath Syst Pharm, 65, 1648, 2008;Wong, Adv Drug Del Rev, 60, 939, 2008; Minton, Nutrition, 14, 251, 1998;Tian, Polym Int, 55, 405, 2006). Instructions for use of an injectablepharmaceutical solution contraindicate injection into the vasculature orflowing blood if the injectable pharmaceutical solution is turbid orcontains precipitates.

There remains a need for improved vascular-based therapies to treat avariety of vascular conditions. The improved therapies would be easilyimplemented and would obviate mechanically or chemically induced traumato the vascular treatment site. The improved therapies would allow foradministration of thixotropic, turbid, bioactive agent-containing gelmaterials to vascular tissue at a vascular treatment site. The gelmaterial would readily release one or more bioactive agents contained bythe gel material to vascular tissue in need of treatment or repair. Thegel material would dissolve in the flowing blood without occludingvascular structures located distally (i.e., downstream) to theadministration site. The therapies could be applied prophylactically,interventionally, surgically, or endovascularly.

SUMMARY OF THE INVENTION

The present invention relates to methods of treating or preventing avascular condition with a thixotropic, turbid, bioactiveagent-containing gel material. The method can also be used to treat orrepair traumatized vascular structures. The gel material will readilydeliver one or more bioactive agents contained by the gel material to adiseased or disease-prone vascular treatment site in need of treatmentor repair. In the method, the gel material is capable of being directlyinjected into luminal spaces of blood vessels and other fluid-conductinganatomical structures with little or no mechanical or chemical trauma tovascular tissues of the vascular treatment site. After contact with thevascular tissues, the gel material will substantially dissolve inflowing blood without occluding vascular structures located distally(i.e., downstream) to the administration site. The method could beapplied prophylactically, interventionally, surgically, orendovascularly. The method does not require a high degree of skill toperform. On the contrary, the method relies on simple injection of thegel material within a vascular structure for delivery of apharmaceutical or other bioactive agent to vascular tissue in need oftreatment.

The gel material used in the method is a thixotropic, turbid, gelmaterial, having high viscosity at low shear, and therefore, coherentlyresides in luminal spaces of a blood vessel under conditions of low orno blood flow. Upon resumption of flowing blood in the treated bloodvessel, the resultant fluid shear force converts the gel material to alow viscosity, blood-soluble composition that is substantially dissolvedin flowing blood. Consequently, the gel material is readily andessentially removed from the vascular treatment site uponre-establishment of flowing blood without obstructing vascularstructures located downstream of the treatment site.

The method allows for surgical, endovascular, and minimally-invasivedelivery of a wide variety of pharmaceuticals and biologics forprophylactic and interventional vascular therapy. Preferred bioactiveagents are pharmacologically and biologically active entities thatinhibit a variety of vascular pathologies including, but not limited to,intimal hyperplasia. The gel material can be delivered through needleand catheter based devices including, but not limited to, ballooncatheters, infusion catheters, and micro-injection systems. In additionto placement of the gel material within a blood conduit, the compositioncan be applied to blood contacting surfaces of medical devices,including, but not limited to, vascular grafts, stents, stent-grafts,and balloons.

One embodiment of the present invention relates to a method of treatinga vascular condition by providing a thixotropic, turbid, gel materialcontaining at least one bioactive agent capable of treating vasculartissue in sufficient amounts to treat said vascular condition in saidvascular tissue upon release of said bioactive agent from said gelmaterial, administering said gel material to a vascular treatment sitewithin an interior space of a blood vessel, and allowing said gelmaterial to remain at said vascular treatment site for a dwell timesufficient to release said bioactive agent from said gel material. Inaddition, the gel material does not occlude vascular structures uponintroduction into flowing blood.

Another embodiment of the present invention relates to a method oftreating a vascular condition by providing a thixotropic, turbid, gelmaterial containing at least one bioactive agent capable of treatingintimal hyperplasia in sufficient amounts to inhibit intimal hyperplasiaupon release of said bioactive agent from said gel material,administering said gel material to a vascular treatment site within aninterior space of a blood vessel, and allowing said gel material toremain at said vascular treatment site for a dwell time sufficient torelease said bioactive agent from said gel material. In addition, thegel material does not occlude vascular structures upon introduction intoflowing blood.

Another embodiment of the present invention relates to a method oftreating a vascular condition by providing a cyclodextrin polymer-basedcomposition comprising cyclodextrin, a polymer, and a pharmacologicallyeffective amount of at least one drug; wherein the polymer comprisesethylene glycol units that can form a hydrogel with the cyclodextrin,wherein the cyclodextrin and the polymer self-assemble to form ahydrogel by spontaneous association and are present in the compositionin respective amounts effective to make the hydrogel thixotropic andinjectable into the body of a person through a needle, and wherein thehydrogel forms a matrix for the drug such that when the composition isinjected into the body of the person, the drug is released from thehydrogel in a sustained manner, administering said hydrogel material toa vascular treatment site within an interior space of a blood vessel,and allowing said hydrogel material to remain at said vascular treatmentsite for a dwell time sufficient to release said bioactive agent fromsaid hydrogel material.

Other embodiments of the present invention relate to medical deviceshaving thixotropic, turbid, gel materials, as described herein, appliedto at least a portion of the medical device. The medical devices areeither implantable devices or are devices used to deliver one or morebioactive agents to a specific site in the body. A preferred medicaldevice of the present invention comprises a cyclodextrin polymer-basedcomposition comprising cyclodextrin, a polymer, and a pharmacologicallyeffective amount of at least one drug, wherein the polymer comprisesethylene glycol units that can form a hydrogel with the cyclodextrin,wherein the cyclodextrin and the polymer self-assemble to form ahydrogel by spontaneous association and are present in the compositionin respective amounts effective to make the hydrogel thixotropic, andwherein said hydrogel is attached, or otherwise applied, to at least aportion of a medical device. Further embodiments include at least onebioactive agent combined with the hydrogel. Preferably, the bioactiveagent is capable of treating vascular tissue and is present in thehydrogel in sufficient amounts to treat a vascular condition uponrelease of the bioactive agent from the hydrogel combined therewith.

Other features and advantages of the invention will be apparent from thefollowing description and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a table of data.

FIG. 2 shows two photographs (a) and (b), each containing histologicaldata.

FIG. 3 shows two photographs (a) and (b), each containing histologicaldata.

FIG. 4 shows a table of data.

FIG. 5 shows four photographs (a), (b), (c), and (d).

FIG. 6A shows a medical device having at least one thixotropic, turbid,gel material applied to at least a portion of the medical device.

FIG. 6B shows a medical device having at least one thixotropic, turbid,gel material applied to at least a portion of the medical device.

FIG. 6C shows a medical device having at least one thixotropic, turbid,gel material applied to at least a portion of the medical device.

FIG. 7A shows a catheter-based device having at least one thixotropic,turbid, gel material applied to at least a portion of the catheter-baseddevice.

FIG. 7B shows a catheter-based device having at least one thixotropic,turbid, gel material applied to at least a portion of the catheter-baseddevice.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to methods of treating or preventing avascular condition with a thixotropic, turbid, bioactiveagent-containing gel material.

The invention utilizes turbid gel materials having thixotropicproperties. The thixotropic properties of the gel materials permit thecompositions to undergo changes in viscosity in response to the presenceor absence of shear forces applied to the compositions. When a shearforce is applied to the gel material by injection of the gel materialfrom a needle-containing syringe, the viscosity of the composition isaltered to a point where the composition can easily pass through theneedle-containing syringe. When the shear force is removed from the gelmaterial, the viscosity of the composition is altered to a point wherethe composition will not flow under the influence of its own weight. Asuitable gel material for use in the present invention is a materialthat can be made to flow under shear force, but exhibits no flow underthe influence of its own weight under non-shear conditions.

When the gel material containing a bioactive agent is placed inside ablood vessel to form an indwelling composition, the bioactive agentmoves from the indwelling composition to tissues of the bloodvessel—independent of the viscosity of the gel material Once sufficienttime has elapsed for a desired amount of bioactive agent to be deliveredfrom the indwelling composition to a vascular treatment site in need oftreatment or repair, the indwelling composition is exposed to shearforces to decrease the viscosity of the gel material and begin a processof dissolution of the gel material into flowing blood. In the presentinvention, shear force is applied to the indwelling composition bypermitting blood to flow through the vascular treatment site containingthe indwelling composition. As the viscosity of the gel material isreduced, the indwelling composition begins to substantially dissolve inthe flowing blood. Substantial dissolution of the gel material inflowing blood continues until essentially all of the gel material hasbeen removed from the treatment site and is present in a substantiallyto completely dissolved state in flowing blood. Once present in flowingblood, the gel material does not diminish, limit, occlude, or otherwiseinterfere with the flow of blood in vascular structures located distally(i.e., downstream) to the vascular treatment site.

In a preferred embodiment, a thixotropic, turbid, bioactiveagent-containing gel material is administered to a vascular treatmentsite within an isolated interior space of an exsanguinated fluidconduit. The gel material is allowed to reside in the isolated interiorspace for a period of time (“dwell time”). The dwell time for the gelmaterial is primarily determined by the rate at which a bioactive agentis delivered from the gel material to vascular tissues at a treatmentsite. The dwell time for the gel material can also be determined by thetiming and sequencing of a similar procedure at another vasculartreatment site or other medical procedures being performed at the sametime. Transfer of bioactive agents from a gel material used in thepresent invention to vascular and other tissues occurs in a range ofabout 5 seconds to greater than about one hour. Regardless of thedelivery rate of bioactive agents to a vascular treatment site in needof treatment by the present invention, a similar or different surgicalprocedure to another vascular treatment site can increase the dwell timeof the gel material at the vascular tissue treatment site.

Once sufficient bioactive agent has been delivered to a vasculartreatment site in need of treatment according to methods of the presentinvention, blood is allowed to re-enter the isolated interior space ofthe fluid conduit. Shear forces applied to the thixotropic gel materialby the flowing blood cause the viscosity of the indwelling compositionto decrease. The decrease in viscosity of the gel material causes theindwelling composition to dissolve substantially in blood flowingthrough the treated fluid conduit. Substantial dissolution of the gelmaterial in flowing blood is sufficient to prevent blockage, orocclusion, of vascular structures located distally (i.e., downstream) ofthe vascular treatment site.

A “gel material” is a material that includes at least two components, asolvent component and a polymer chain component. The term “hydrogel” asused herein means a material that includes at least two components, anaqueous solvent component, and a polymer chain component. The gelmaterial of the present invention does not flow under the influence ofits own weight. This property is observable by the unaided eye whenabout 5 ml of gel material is placed into a 13 mm by 100 mm standardglass test tube and inverted 180 degrees for a few seconds.

In addition to thixotropy, the gel material employed in the presentinvention is turbid. The term “turbid” means the gel material appearshazy, translucent, cloudy, opalescent, or opaque to the unaided eye. Theturbidity of gel materials used in the present invention can bedetermined when about 5 ml of gel material is placed into a 13 mm by 100mm standard glass test tube and viewed by the unaided eye at a rightangle to an illuminating light source and against a dark background.

The terms “thixotropic” and “thixotropy” refer to physical properties ofparticular chemical entities. A chemical entity is thixotropic when thechemical entity exhibits behavior in which viscosity of the chemicalentity decreases under an applied shear force and then increases inviscosity when the applied shear force is removed. Shear forces can beapplied to thixotropic gel materials by methods including, but notlimited to, shaking, stirring, exposure to fluid flow, and mechanicalexpansion in surface area. Thixotropy can be assessed using methods suchas rheometry and viscometry.

The term “vascular condition” includes, but is not limited to, vascularinjury, vascular prophylactic intervention, vascular disease, intimalhyperplasia, phlebitis, vulnerable plaques, carotid plaques, coronaryplaque, vascular plaque, aneurismal disease, vascular dissections,atherosclerotic plaques, atherosclerotic lesions, vascular infection,and vascular sepsis.

The term “inflammation” as used herein refers to a physiologicalresponse by a mammalian body to surgery, injury, irritation, orinfection. An inflammatory response involves complex biologicalactivities at chemical, cellular, tissue, and organ levels. Generally,an inflammatory response is a protective attempt to remove an injuriousstimulus, as well as to initiate a healing process for the diseased ortraumatized tissue.

Suitable polymer chain components for the thixotropic turbid gelmaterials in the present invention are natural and synthetic polymersthat are capable of forming a thixotropic, turbid, gel. The polymerchain components include but are not limited to polyethers such aspolyethylene glycol, polypropylene glycol, poly(ethyleneglycol-co-propylene glycol), copolymers of polyethylene glycol, andcopolymers of polypropylene glycol; polyols such as polyvinyl alcoholand polyallyl alcohol; polyanions such as polyacrylic acid andpoly(methacrylic acid); polyanionic polysaccharides such as alginate,heparin, heparin sulfate, dextran sulfate, xanthan, carrageenan, gumarabic, tragacanth, arabinogalactan, and pectin; neutral polysaccharidessuch as agar, agarose, hyaluronic acid, carboxymethylcellulose, anddextran; macrocyclic polysaccharides such as cyclodextrin andhydroxypropyl cyclodextrin; polycations such as poly(lysine),poly(allylamine), poly(ethyleneimine), poly(guanidine), poly(vinylamine), α,ω-polyethylene glycol-diamine, and poly(quaternary amine);polyanionic polysaccharides such as chitin and chitosan;polyacrylonitriles such as hydrolyzed polyacrylonitrile,poly(acrylamide-co-acrylonitrile), and their copolymers; and proteinbased polymers such as gelatin, collagen, thrombin, and fibrin.

In one embodiment, the gel materials are composed of α-cyclodextrin(αCD) and polyethylene glycol (PEG). Such gel materials are thixotropicand turbid.

Suitable bioactive agents in the thixotropic turbid gel materials in thepresent invention are biologically and pharmaceutically active entitiesthat exert a desired effect upon the native cells, microbes,intercellular environments, and tissues of the vascular treatment site.The gel material may include a solubilizing agent to improve orotherwise alter the solubility of the bioactive agent in the gelmaterial. The gel material may include a permeability agent to improveor otherwise alter the delivery of the bioactive active agent tovascular tissues. The bioactive agent may consist of simple molecules,macromolecules, inorganic molecules, and complex biological entitiessuch as cells, tissues, or tissue aggregates.

Bioactive agents suitable for use in the present invention include, butare not limited to, protein based molecules such as enzymes, growthfactors, proteases, glycoproteins, and cytokines; nucleic acid basedmolecules such as DNA, RNA, genes, gene fragments, ribozymes, andnucleic acids; carbohydrate based molecules such as glucose, glycogen,cyclodextrin, and heparin; lipid based molecules such as cholesterol andprostaglandin; complex biological entities such as extracellular matrix,viruses, virenos, prions, cells, tissues, and tissue aggregates; andorganic molecules such as hormones, organic catalysts, organometallics,and oleophobics. Other bioactive agents include drugs including, but notlimited to, cardiovascular agents, chemotherapeutics, antimicrobials,antibiotics, anesthetics, anticoagulants, hem ostatics, antihistamines,antitumors, antilipids, antifungals, antimycotics, antipyretics,vasodilators, hypertensive agents, oxygen free radical scavengers,antivirals, analgesics, antiproliferatives, antiinflammatories,diagnostic agents, visualization agents, angiographic contrast agents,phase contrast agents, and radiopaque agents. Other bioactive agentsinclude but are not limited to antirestenotic drugs including, but notlimited, to pimecrolimus, cytochalasin, dicumarol, cyclosporine,latrunculin A, methotrexate, tacrolimus, halofuginone, mycophenolicacid, genistein, batimistat, dexamethasone, cudraflavone, simvastatin,prednisolone, doxorubicin, bromopyruvic acid, carvedilol, mitoxantrone,tranilast, etoposide, hirudin, trapidil, mitomycin C, abciximab,cilostazol, irinotecan, estradiol, diaziquone, dipyridamole, melatonin,colchicine, nifedipine, vitamin E, paclitaxol, diltiazem, vinblastine,verapamil, vincristine, rapamycin, angiopeptin, everolimus, heat shockproteins, zotarolimus, nitroglycerin, and prednisone.

Bioactive agents used in the present invention inhibit or preventpathological vascular conditions. In certain embodiments, the bioactiveagents have anti-inflammatory properties, inhibit proliferation ofsmooth muscle cells, and/or influence gene expression in vasculartissue. In one embodiment, the bioactive agent is dexamethasone.Dexamethasone is considered both a smooth muscle cell anti-proliferativeagent and an anti-inflammatory agent.

In an embodiment of the present invention, a need for treating one ormore vascular structures is determined. The vascular structure, or otherbody fluid conduit, designated for treatment is surgically exposed usingconventional techniques. Once the vascular structure is surgicallyexposed, means for stopping blood flow in the structure are applied toisolate the structure, thus defining the vascular treatment site. Suchmeans include, but are not limited to, ligatures, ties, clamps, sutures,staples, or other devices capable of applying a compressive force to avascular structure sufficient to stop flow of blood in the vascularstructure.

The vascular treatment site is accessed with a needle-containing syringeand any blood or other fluid residing in the vascular treatment site isremoved through the needle-containing syringe.

A thixotropic, turbid, bioactive agent-containing gel material, preparedas described herein, is placed in a needle-containing syringe. Toadminister the gel material to a vascular treatment site at a vascularstructure, the open end of the needle is inserted inside theexsanguinated, vascular treatment site, and the gel material is injectedinside the vascular structure and allowed to reside for a determineddwell time. As shear force is applied to the gel material duringinjection, the viscosity of the gel material decreases and the gelmaterial flows through the needle into the interior space (luminalspace) of the vascular treatment site. As the gel material fills thevascular treatment site, the shear forces applied to the gel materialduring injection diminish. As shear forces on the gel material diminish,the viscosity of the gel material increases, and the gel material willnot flow under the influence of its own weight.

Once the gel material is inside a vascular treatment site, any bioactiveagents associated with the gel material can move from the gel materialto tissues of the vascular treatment site. The delivery of bioactiveagent from the gel material to vascular tissue can occur within a rangeof about 5 seconds to greater than about one hour (see e.g. Example 4,infra). The dwell time of the gel material can be chosen to be longerthan is needed to deliver sufficient amounts of bioactive agent tovascular tissue of a vascular treatment site to treat a vascularcondition.

Following a dwell time sufficient for substantial bioactive agent to bedelivered to a vascular treatment site to treat the vascular tissue, themeans for stopping blood flow in the isolated vascular structure areremoved. Once the means are removed, flowing blood through the vasculartreatment site is re-established. As flowing blood is re-established inthe vascular treatment site, shear force is once again applied to thegel material. As shear force is applied to the gel material, theviscosity of the gel material is decreased causing the gel material tobegin substantially dissolving in the flowing blood. If the isolated,exsanguinated, vascular treatment site is transparent or translucent,then substantial dissolution of the gel material in flowing blood can beobserved through the vascular treatment site with the naked eye.Substantial dissolution of the gel material continues until essentiallyall the gel material is removed from the vascular treatment site and issubstantially dissolved in the blood stream. The substantially dissolvedgel material does not limit, occlude, or otherwise diminish blood flowin vascular structures located distally (i.e., downstream) to thevascular treatment site.

Once flowing blood is re-established in the treated vascular treatmentsite, the vascular treatment site is surgically closed, and any othernecessary surgical procedures performed.

Another embodiment of the method of the present invention can bepracticed using interventional techniques. Interventional techniquesroutinely involve minimally invasive procedures. Often this technique isinitiated by a puncture or cut-down of a vascular structure andinsertion of a catheter through an interventional access site into thevascular structure. Interventional access sites may include, but are notlimited to, access through an implanted vascular prosthesis, brachialartery, carotid artery, iliac artery, femoral artery, aorta, and otherarterial or venous sites.

After insertion of a catheter through an interventional access site intothe vascular structure, the catheter can then be guided to a site with avascular condition in need of vascular treatment (i.e., a vasculartreatment site), from the interventional access site. The vasculartreatment site may include, but is not limited to, vascular conduitssuch as a blood vessel, a vascular graft, a vascular stent, a vascularfilter, a vascular anastomosis, and a vascular stent graft.

One embodiment of the method of the present invention relates to aninterventional treatment of a vascular condition involving theadministration of a gel material to a vascular treatment site byinjection through a catheter. The gel material may be injected directlyto the vascular treatment site with or without prior occlusion offlowing blood at the vascular treatment site.

Another embodiment of the present invention relates to catheterinjection of a thixotropic, turbid, bioactive agent-containing gelmaterial through a medical device, including, but not limited to,commercially available catheters, single balloon catheters,needle-studded catheters, infusion catheters, balloon catheters, doubleballoon catheters, angioplasty balloon, weeping balloon catheters,infusion balloon catheters, and needle studded balloon catheters.

In another embodiment, the thixotropic, turbid, bioactiveagent-containing gel material may be pre-applied to an implantablemedical device, vascular prosthesis, or catheter-based device prior tocatheter insertion into a vascular structure. For example, thethixotropic, turbid, bioactive agent-containing gel material may beapplied manually to an implantable medical device, vascular prosthesis,or catheter-based device including, but not limited to, a stent, stentgraft, vascular graft, angioplasty balloon, needle studded balloon, andother vascular prosthesis. The application may be continuous ordiscontinuous, covering at least a portion of the implantable medicaldevice. Interventional vascular access is then used to place thecatheter-based device at a vascular treatment site. The catheter-baseddevice is then placed at the vascular treatment site allowing fordelivery of the thixotropic, turbid, bioactive agent-containing gelmaterial to the vascular treatment site.

FIG. 6A depicts a cross section of a medical device 16 as from a stent,stent-graft, graft, balloon, or other vascular prosthesis, having athixotropic, turbid gel material 12 of the present invention applied tothe medical device 16. Gel material 12 is applied to the entire surfaceof the medical device 16 to create an applicated medical device 10. Theapplication may be continuous or discontinuous.

FIG. 6B depicts a cross section of a medical device 16 as from a stent,stent-graft, graft, balloon, or other vascular prostheses, having athixotropic, turbid gel material 12 of the present invention applied tothe medical device 16. Gel material 12 is applied to one surface of themedical device 16 to create an applicated medical device 10. Theapplication may be continuous or discontinuous

FIG. 6C depicts a cross section of a medical device 16, having a firstapplication 12 c and a second application 12 d of the gel material ofthe present invention. Gel material 12 c and 12 d is applied to opposingsides of the medical device 16 to create an applicated medical device10. The application may be continuous or discontinuous.

In another embodiment, the thixotropic, turbid, bioactiveagent-containing gel material may be pre-applied to a catheter-baseddevice prior to catheter insertion into a vascular structure. Forexample, the thixotropic, turbid, bioactive agent-containing gelmaterial may be applied manually to a catheter-based device including,but not limited to, a stent, stent graft, angioplasty balloon, needlestudded balloon, and other vascular prosthesis. The application may becontinuous or discontinuous, covering at least a portion of theimplantable medical device. Catheter-based devices have a first diameterand a first surface area prior to and during insertion of thecatheter-based devices into a vascular structure. After insertion intothe vascular structure, the catheter-based devices are mechanicallyexpanded to a second diameter and a second surface area within thevascular structure. The thixotropic properties of the gel materialspermit the compositions to undergo changes in viscosity in response tothe presence or absence of shear forces applied to the compositions.When a shear force is applied to the gel material during mechanicalexpansion of the catheter-based device, the viscosity of the compositionis decreased to a point where the composition can readily deform fromthe first surface area to the second surface area as the catheter-baseddevice is mechanically expanded. When the shear force is removed fromthe gel material after mechanical expansion of the catheter-baseddevice, the viscosity of the composition is altered to a point where thecomposition will not flow under the influence of its own weight and willremain at the second surface area. The catheter-based device is placedat a vascular treatment site allowing for delivery of the thixotropic,turbid, bioactive agent-containing gel material to the vasculartreatment site during and/or after expansion of the catheter-baseddevice. A suitable gel material for use in the present invention is amaterial that can be made to flow under shear force, but exhibits noflow under the influence of its own weight under non-shear conditions.

FIG. 7A depicts a cross section of catheter-based device 16 as from astent, stent-graft, balloon, or other vascular prosthesis, surroundingcatheter 14, and having a thixotropic, turbid gel material 12 of thepresent invention applied to the catheter-based device 16. Gel material12 is applied to a surface of catheter-based device 16 to create anapplicated catheter-based device 10 of a first diameter and a firstsurface area. The application may be continuous or discontinuous

FIG. 7B depicts a cross section of the same catheter-based device shownby FIG. 7A, except that catheter-based device 16 is expanded to a seconddiameter and a second surface area.

In another embodiment, incorporation of a bioactive agent in the form ofan angiographic contrast agent within the thixotropic, turbid, bioactiveagent-containing gel material permits an angiographic visualization ofthe gel material at a vascular treatment site. The contrast agent may beincorporated within the thixotropic, turbid, bioactive agent-containinggel material through admixing, reformulation, combination, directsolubilization of the agent within the gel material, or other methods ofincorporating said contrast agent in said gel material. Thesethixotropic, turbid, bioactive agent-containing gel materials arevisualized at a vascular treatment site using angiography.

Other embodiments of thixotropic, turbid, bioactive agent-containing gelmaterials capable of treating vascular tissue in sufficient amounts totreat a vascular condition may include but are not limited to gelmaterials made from polyethylene glycol, α-cyclodextrin,hydroxypropyl-β-cyclodextrin (HPβCD), and a bioactive agent; polyvinylalcohol, sodium borate, polyoxyethylene sorbitol ester, and a bioactiveagent; sodium alginate, calcium chloride, hydroxypropyl-β-cyclodextrin,and a bioactive agent; and dextran, potassium chloride,hydroxypropyl-β-cyclodextrin (HPβCD), and a bioactive agent.

A preferred thixotropic, turbid, bioactive agent-containing gel materialfor use in the present invention is disclosed by Li et al. (U.S. PatentApplication Publication 2002/0019369), which is incorporated herein byreference.

EXAMPLES Example 1

This Example describes the preparation of a thixotropic, turbid gelmaterial that contains a bioactive agent capable of treating vasculartissue in sufficient amounts to treat a vascular condition.

A first solution (referred herein as Solution 1A) was prepared by mixingphosphate buffered saline (PBS) (0.15M NaCl, pH 7.4, InvitrogenCorporation Carlsbad, Calif.) with 0.40 g/mlhydroxypropyl-β-cyclodextrin (HPβCD) (Sigma-Aldrich, St. Louis, Mo.) and0.20 g/ml alpha-cyclodextrin (αCD) (Sigma-Aldrich) through stirring andheating (60° C.), followed by adding dexamethasone (Pharmacia & UpjohnCompany, Kalamazoo, Mich.) at 20 mg/ml with stirring and heating (60°C.). Solution 1A did not form a gel material and was not turbid.

A second solution (referred herein as Solution 1B) was prepared bydissolving polyethylene glycol (PEG, Dow Chemical, Midland, Mich.) ofaverage Mn=8 kDa (0.26 g/ml) with PBS. Solution 1B did not form a gelmaterial and was not turbid.

Equal volumes of Solution 1A and Solution 1B were combined with mixingto form Gel Material A. Gel Material A was turbid, and was opaque andwhite in appearance.

Example 2

This Example describes preparation of a thixotropic, turbid gel materialthat contains a bioactive agent capable of treating vascular tissue insufficient amounts to treat a vascular condition.

A first solution (Solution 2A) was prepared by mixing PBS (0.15M NaCl,pH 7.4, Invitrogen) with 0.40 g/ml hydroxypropyl-β-cyclodextrin (HPβCD)(Sigma-Aldrich, St. Louis, Mo.) and 0.20 g/ml alpha-cyclodextrin (αCD)(Sigma-Aldrich) through stirring and heating (60° C.), followed byadding 17β-estradiol (20 mg/ml) (Sigma-Aldrich) by stirring and heating(60° C.). Solution 2A did not form a gel material and was not turbid.

A second solution (Solution 2B) was prepared by dissolving PEG (DowChemical, Midland, Mich.) of average Mn=8 kDa (0.26 g/ml) in PBS.Solution 2B did not form a gel material and was not turbid.

Equal volumes of Solution 2A and Solution 2B were combined with mixingto form Gel Material B. Gel Material B was turbid, and was opaque andwhite in appearance.

Example 3

This Example describes preparation of a thixotropic, turbid gel materialthat contains a bioactive agent capable of treating vascular tissue insufficient amounts to treat a vascular condition.

A first solution (Solution 3A) was prepared by mixing PBS (0.15M NaCl,pH 7.4) with 0.40 g/ml hydroxypropyl-β-cyclodextrin (HPβCD)(Sigma-Aldrich, St. Louis, Mo.) and 0.20 g/ml alpha-cyclodextrin (αCD)(Sigma-Aldrich) through stirring and heating (60° C.), followed byadding dicumarol (0.67 mg/ml) (Sigma-Aldrich) by stirring and heating(60° C.). Solution 3A did not form a gel material and was not turbid.

A second solution (Solution 3B) was prepared by dissolving of PEG (Dow)of average Mn=8 kDa (0.26 g/ml) in PBS. Solution 3B did not form a gelmaterial and was not turbid.

Equal volumes of solutions 3A and 3B were combined with mixing to formGel Material C. Gel Material C was turbid, and was opaque and white inappearance.

Example 4

This Example describes in vivo delivery of dexamethasone to venoustissue (“treated vascular tissue”) according to a method of the presentinvention.

A thixotropic, turbid gel material (herein referred to as Gel Material4A) was made by the following steps.

A first solution (referred herein as Solution 4A) was prepared by mixingphosphate buffered saline (PBS) (0.15M NaCl, pH 7.4, InvitrogenCorporation Carlsbad, Calif.) with 0.40 g/mlhydroxypropyl-β-cyclodextrin (HPβCD) (Sigma-Aldrich, St. Louis, Mo.) and0.20 g/ml alpha-cyclodextrin (αCD) (Sigma-Aldrich) through stirring andheating (60° C.). Solution 4A did not form a gel material and was notturbid.

Then, a dexamethasone mixture was made by combining tritium-labeleddexamethasone (Perkin Elmer, Waltham, Mass. and unlabeled dexamethasone(Pharmacia & Upjohn Company) at a ratio of approximately 18 μg/g.Solution 4B was formed by solubilizing approximately 20 mg/ml of thedexamethasone mixture in Solution 4A. Solution 4B did not form a gelmaterial and was not turbid.

Solution 4C was prepared by dissolving polyethylene glycol (PEG, DowChemical, Midland, Mich.) of average Mn=8 kDa (0.26 g/ml) with PBS.Solution 4C did not form a gel material and was not turbid.

Equal volumes of Solution 4B and Solution 4C were combined with mixingto form Gel Material 4A. Gel Material 4A was turbid, and was opaque andwhite in appearance.

Healthy canines were anaesthetized. A five centimeter (5 cm) segment ofcanine femoral vein was surgically exposed. Blood flow in the segmentwas stopped by constriction of the vein with rubber ties positioned atthe proximal and distal ends of the segment. A vascular tissue treatmentsite was the length of vessel between the rubber ties. The vasculartreatment site was cannulated. Blood within the vessel lumen waswithdrawn at the cannulation using a syringe. The lumen of the vasculartreatment site was irrigated three times with saline applied with asyringe at the cannulation. One to three milliliters (1 to 3 ml) of GelMaterial 4A was injected at the cannulation and allowed to contact theblood vessel lumen for a treatment period of two (2), ten (10), or forty(40) minutes. No leakage of the Gel Material 4A from any treated vesselsegment was observed during the treatment period.

After the designated treatment period, the ties were removed from eachblood vessel segment, and blood flow was permitted to resume in thevascular treatment site for one hour (1 hr). Canine veins are relativelytransparent, enabling observation with the unaided eye of Gel Material4A administration and removal from the vascular treatment site. Uponre-establishment of blood flow in the vascular treatment site, GelMaterial 4A was observed to substantially dissolve within approximatelyone minute (1 min). After one hour (1 hr) of blood flow, the vasculartreatment site was harvested and washed thoroughly with saline.

Tissue sections (approximately 1 cm in length) were taken from eachvascular treatment site and digested overnight in five milliliters (5ml) of Solvable digestion fluid (Perkin Elmer). Fifteen milliliters (15ml) of HiSafe 2 (Perkin Elmer), a scintillation cocktail, was added tothe tissue sections to permit scintillation counting and quantificationof beta radiation emitted by the tritium-labeled dexamethasone withineach section.

A second group of healthy canines was anaesthetized. Control veinsections (approximately 1 cm in length) were obtained from thesecanines. The control vein sections were digested overnight in 5 ml ofSolvable digestion fluid (Perkin Elmer). Known amounts oftritium-labeled dexamethasone were added to the digestion fluid. Fifteenmilliliters (15 ml) of HiSafe 2 (Perkin Elmer), was added to the controlvein sections to permit scintillation counting and quantification of thebeta-radiation emitted by the tritium-labeled dexamethasone within eachcontrol vein section.

A scintillation counter (Perkin Elmer) was used to measure the betaradiation (disintegrations per minute) emitted by each control veinsection and to generate a linear standard curve of disintegrations perminute as a function of the tritium-labeled dexamethasone within eachsection. Radiation levels (disintegrations per minute) from the tissuesection were then compared to the standard curve to calculatetritium-labeled dexamethasone retention. The total amount ofdexamethasone retained in each tissue section was determined bycorrelation of the total amount of dexamethasone in Gel Material 4A tothe measured amount of tritium-labeled dexamethasone in eachexperimental tissue section.

FIG. 1 shows the resulting amount of total dexamethasone in theexperimental tissue sections. As shown, when Gel Material 4A containingdexamethasone was allowed to contact a blood vessel lumen devoid ofblood for two minutes (2 min), an average of 9.3 μg dexamethasone/gtissue remained in the tissue section after 1 h blood flow. The vasculartreatment site included the tissue sections. Therefore, an average of9.3 μg dexamethasone/g tissue was retained at the vascular treatmentsite at 1 h.

Example 5

This Example demonstrates the use of a thixotropic, turbid gel materialin canine jugular veins (“treated vascular tissue”). This example alsoillustrates dissolution of a gel material in the blood stream that doesnot occlude vascular structures upon introduction to flowing blood.

Healthy canines were anaesthetized. A five centimeter (5 cm) segment ofcanine jugular vein was surgically exposed. Blood flow in the segmentwas stopped by constriction of the vein with rubber ties positioned atthe proximal and distal ends of the segment. A vascular tissue treatmentsite was the length of vessel between the rubber ties. The vasculartreatment site was cannulated. Blood within the vessel lumen waswithdrawn at the cannulation using a syringe. The lumen of the vasculartreatment site was irrigated three times with saline applied with asyringe at the cannulation. Three to four milliliters (3 to 4 ml) of GelMaterial A (described in Example 1, supra) was injected at thecannulation and allowed to contact the blood vessel lumen for atreatment period of forty (40) minutes. No leakage of the Gel Material Afrom any treated vessel segment was observed during the treatmentperiod.

After the designated treatment period, the ties were removed from eachblood vessel segment, and blood flow was permitted to resume in thevascular treatment site for one hour (1 hr). Canine veins are relativelytransparent, enabling observation with the unaided eye of Gel Material Aadministration and removal from the vascular treatment site. Uponre-establishment of blood flow in the vascular treatment site, GelMaterial A was observed to substantially dissolve within approximatelyone minute (1 min). All canines remained in-life for one hour (1 h)after re-establishment of blood flow in treatment site.

After one hour (1hr) of blood flow, the vascular treatment site washarvested and washed thoroughly with saline. Upon visible inspection, noGel Material A was observable on luminal surfaces of any treatment site.Tissue sections (approximately 1 cm in length) were taken from eachvascular treatment site. A histological examination (see FIG. 2) ofthese sections revealed a normal appearance of these sections.

The heart and lungs of canines treated with Gel Material A in thepresent Example were surgically excised. A pathological examination ofthe heart and lungs revealed no evidence of embolism or occlusion inthese organs, indicating that Gel Material A dissolution in the bloodstream did not limit blood flow in vascular structures located distal(i.e., downstream) to the vascular tissue treatment site. These resultsdemonstrate that the method of administering the gel material did notocclude vascular structures upon introduction into flowing blood.

Example 6

This Example demonstrates the use of a thixotropic, turbid gel materialin canine femoral veins (“treated vascular tissue”). This example alsoillustrates dissolution of a gel material in the blood stream that doesnot occlude vascular structures upon introduction to flowing blood.

Healthy canines were anaesthetized. A five centimeter (5 cm) segment ofcanine femoral vein was surgically exposed. Blood flow in the segmentwas stopped by constriction of the vein with rubber ties positioned atthe proximal and distal ends of the segment. A vascular tissue treatmentsite was the length of vessel between the rubber ties. The vasculartreatment site was cannulated. Blood within the vessel lumen waswithdrawn at the cannulation using a syringe. The lumen of the vasculartreatment site was irrigated three times with saline applied with asyringe at the cannulation. One to three milliliters (1 to 3 ml) of GelMaterial A (described in Example 1, supra) was injected at thecannulation and allowed to contact the blood vessel lumen for atreatment period of forty (40) minutes. No leakage of the Gel Material Afrom any treated vessel segment was observed during the treatmentperiod.

After the designated treatment period, the ties were removed from eachblood vessel segment, and blood flow was permitted to resume in thevascular treatment site. Canine veins are relatively transparent,enabling observation with the unaided eye of Gel Material Aadministration and removal from the vascular treatment site. Uponre-establishment of blood flow in the vascular treatment site, GelMaterial A was observed to substantially dissolve within approximatelyone minute (1 min).

After re-establishment of blood flow in the treatment site, subcutaneoustissue and skin surrounding the treatment site were closed with sutures.All canines remained in-life for fourteen days (14 d).

After fourteen days (14 d), all canines were euthanized. Then, thevascular treatment site was harvested and washed thoroughly with saline.Upon visible inspection, no Gel Material A was observable on luminalsurfaces of any treatment site. Tissue sections (approximately 1 cm inlength) were taken from each vascular treatment site. Histologicalexamination of these sections indicated evidence of a pharmacologicaleffect of the delivered dexamethasone. Specifically, a delayed healingresponse to the surgical trauma of vein cannulation was observed. Tissuesections from uncannulated lengths of the vascular treatment sitedisplayed normal morphology as show in FIG. 3. These findingsdemonstrated the ability of thixotropic, turbid, bioactiveagent-containing gel materials to deliver an effective amount of abiological agent to a vascular treatment site.

The heart and lungs of canines treated with Gel Material A in thepresent Example were also surgically excised at the time of euthanasia.A pathological examination of the heart and lungs revealed no evidenceof embolism or occlusion in these organs, indicating that Gel Material Adissolution in the blood stream did not limit blood flow in vascularstructures located distal (i.e., downstream) to the vascular tissuetreatment site. These results demonstrate that the method ofadministering the gel material did not occlude vascular structures uponintroduction into flowing blood.

Example 7

This Example describes in vivo delivery of estradiol to venous tissue(“treated vascular tissue”) according to a method of the presentinvention.

A thixotropic, turbid gel material (herein referred to as Gel Material7A) was made by the following steps.

A first solution (referred herein as Solution 7A) was prepared by mixingphosphate buffered saline (PBS) (0.15M NaCl, pH 7.4, InvitrogenCorporation Carlsbad, Calif.) with 0.40 g/mlhydroxypropyl-β-cyclodextrin (HPβCD) (Sigma-Aldrich, St. Louis, Mo.) and0.20 g/ml alpha-cyclodextrin (αCD) (Sigma-Aldrich) through stirring andheating (60° C.). Solution 7A did not form a gel material and was notturbid.

Then, an estradiol mixture was made by combining tritium-labeledestradiol (Perkin Elmer) and unlabeled estradiol (Sigma) at a ratio ofapproximately 27 μg/g. A second solution (referred herein as Solution7B) was formed by solubilizing approximately 20 mg/ml of the estradiolmixture in Solution 7A. Solution 7B did not form a gel material and wasnot turbid.

A third solution (referred herein as Solution 7C) was prepared bydissolving polyethylene glycol (PEG, Dow Chemical) of average Mn=8 kDa(0.26 g/ml) with PBS. Solution 7C did not form a gel material and wasnot turbid. Equal volumes of Solution 7B and Solution 7C were combinedwith mixing to form Gel Material 7A. Gel Material 7A was turbid, and wasopaque and white in appearance.

Healthy canines were anaesthetized. A five centimeter (5 cm) segment ofcanine left femoral vein was surgically exposed. Blood flow in thesegment was stopped by constriction of the vein with rubber tiespositioned at the proximal and distal ends of the segment. A vasculartissue treatment site was the length of vessel between the rubber ties.The vascular treatment site was cannulated. Blood within the vessellumen was withdrawn at the cannulation using a syringe. The lumen of thevascular treatment site was irrigated three times with saline appliedwith a syringe at the cannulation. One to three milliliters (1 to 3 ml)of Gel Material 7A was injected at the cannulation and allowed tocontact the blood vessel lumen for a treatment period of forty (40)minutes. No leakage of the Gel Material 7A from any treated vesselsegment was observed during the treatment period.

After the designated treatment period, the ties were removed from eachblood vessel segment, and blood flow was permitted to resume in thevascular treatment site. Canine veins are relatively transparent,enabling observation with the unaided eye of Gel Material 7Aadministration and removal from the vascular treatment site. Uponre-establishment of blood flow in the vascular treatment site, GelMaterial 7A was observed to substantially dissolve within approximatelyone minute (1 min).

After re-establishment of blood flow in the treatment site, subcutaneoustissue and skin surrounding the treatment site were closed with sutures.All canines remained in-life for fourteen days (14 d).

After fourteen days (14 d), all canines treated previously with GelMaterial 7A were again anaesthetized. The vascular treatment site fromthe left femoral vein of each canine was then harvested and washedthoroughly with saline.

With the canines still remaining in-life, a five centimeter (5 cm)segment of the contralateral right femoral vein was surgically exposed.Blood flow in the segment was stopped by constriction of the vein withrubber ties positioned at the proximal and distal ends of the segment. Avascular tissue treatment site was the length of vessel between therubber ties. The vascular treatment site was cannulated. Blood withinthe vessel lumen was withdrawn at the cannulation using a syringe. Thelumen of the vascular treatment site was irrigated three times withsaline applied with a syringe at the cannulation. One to threemilliliters (1 to 3 ml) of Gel Material 7A was injected at thecannulation and allowed to contact the blood vessel lumen for atreatment period of forty (40) minutes. No leakage of the Gel Material7A from any treated vessel segment was observed during the treatmentperiod.

After the designated treatment period, the ties were removed from eachblood vessel segment, and blood flow was permitted to resume in thevascular treatment site for one hour (1 h). Canine veins are relativelytransparent, enabling observation with the unaided eye of Gel Material7A administration and removal from the vascular treatment site. Uponre-establishment of blood flow in the vascular treatment site, GelMaterial 7A was observed to substantially dissolve within approximatelyone minute (1 min).

After one hour (1 hr) of blood flow, the vascular treatment site fromthe right femoral vein was harvested and washed thoroughly with saline.

Tissue sections (approximately 1 cm in length) were taken from allvascular treatment sites (from the left and right femoral veins) anddigested overnight in five milliliters (5 ml) of Solvable digestionfluid (Perkin Elmer). Fifteen milliliters (15 ml) of HiSafe 2 (PerkinElmer), a scintillation cocktail, was added to the tissue sections topermit scintillation counting and quantification of beta radiationemitted by the tritium-labeled estradiol within each section.

A second group of untreated, healthy canines were anaesthetised. Controlvein sections (approximately 1 cm in length) were obtained from thesecanines. The control vein sections were digested overnight in 5 ml ofSolvable digestion fluid (Perkin Elmer). Known amounts oftritium-labeled estradiol were added to the digestion fluid. Fifteenmilliliters (15 ml) of HiSafe 2 (Perkin Elmer), was added to the controlvein sections to permit scintillation counting and quantification of thebeta-radiation emitted by the tritium-labeled estradiol within eachcontrol vein section.

A scintillation counter (Perkin Elmer) was used to measure the betaradiation (disintegrations per minute) emitted by each control veinsection and to generate a linear standard curve of disintegrations perminute as a function of the tritium-labeled estradiol within eachsection. Radiation levels (disintegrations per minute) from the tissuesection were then compared to the standard curve to calculatetritium-labeled estradiol retention. The total amount of estradiolretained in each tissue section was determined by correlation of thetotal amount of estradiol in Gel Material 7A to the measured amount oftritium-labeled estradiol in each experimental tissue section.

FIG. 4 shows the resulting amount of total estradiol in the experimentaltissue sections. As shown, when Gel Material 7A containing estradiol wasallowed to contact a blood vessel lumen devoid of blood for 40 minutes(40 min), an average of 9.8 μg estradiol/g tissue remained in the tissuesection after one hour (1 h blood flow). The vascular treatment siteincluded the tissue sections. Therefore, an average of 9.8 μgestradiol/g tissue was retained in the vascular treatment site at 1 h.

As shown in FIG. 4, when Gel Material 7A containing estradiol wasallowed to contact a blood vessel lumen devoid of blood for 40 minutes(40 min), an average of 0.3 μg estradiol/g tissue remained in the tissuesection after fourteen days (14 d). The vascular treatment site includedthe tissue sections. Therefore, an average 0.3 μg estradiol/g tissue wasretained in the vascular treatment site at fourteen days (14 d).

Example 8

This Example describes preparation of a thixotropic, turbid gel materialthat contains a first bioactive agent capable of treating vasculartissue in sufficient amounts to treat a vascular condition and a secondbioactive agent in the form of a phase contrast agent to assistangiographic visualization of the gel material. This exampledemonstrates visualization of the gel material using angiography.

A first solution (referred herein as Solution 8A) was prepared by mixingPBS with 0.40 g/ml hydroxypropyl-β-cyclodextrin (HPβCD) (Sigma-Aldrich,St. Louis, Mo.) and 0.20 g/ml alpha-cyclodextrin (αCD) (Sigma-Aldrich,St. Louis, Mo.) through stirring and heating (60° C.), followed byadding dexamethasone at 20 mg/ml and 600 mg/ml of iohexol (Hovione,Loures, Portugal) with stirring and heating (60° C.). Solution 8A didnot form a gel material and was not turbid.

A second solution (referred herein as Solution 8B) was prepared bydissolving PEG of average Mn=8kDa (0.26 g/ml) with PBS. Solution 8B didnot form a gel material and was not turbid.

Equal volumes of Solution 8A and Solution 8B were combined with mixingto form Gel Material D. Gel Material D was turbid, and was opaque andwhite in appearance.

A healthy canine was anaesthetized. A segment of canine jugular vein,approximately five centimeters (5 cm) in length, was surgically exposed.Blood flow in the segment was stopped by constriction of the vein withclamps positioned at the proximal and distal ends of the segment. Avascular tissue treatment site was the length of vessel between theclamps. The vascular treatment site was cannulated. Blood within thevessel lumen was withdrawn at the cannulation using a syringe. One tothree milliliters (3 to 4 ml) of Gel Material D was injected at thecannulation and visualized by angiography (FIG. 5c ).

After angiography, the clamps were removed from the blood vesselsegment, and blood flow was permitted to resume in the vasculartreatment site for approximately five minutes (5 min). Then, blood flowin the segment was again stopped by constriction of the vein with clampspositioned at the proximal and distal ends of the segment. A vasculartissue treatment site was the length of vessel between the clamps. Thevascular treatment site was cannulated. Blood within the vessel lumenwas withdrawn at the cannulation using a syringe. One to threemilliliters (3 to 4 ml) of Gel Material A (as described in Example 1,supra, and which contained no phase contrast agent) was injected at thecannulation and visualized by angiography (FIG. 5b ) as a control.

After angiography, the clamps were removed from the blood vesselsegment, and blood flow was permitted to resume in the vasculartreatment site for approximately five minutes (5 min). Then, blood flowin the segment was again stopped by constriction of the vein with clampspositioned at the proximal and distal ends of the segment. A vasculartissue treatment site was the length of vessel between the clamps. Thevascular treatment site was cannulated. Blood within the vessel lumenwas withdrawn at the cannulation using a syringe. One to threemilliliters (3 to 4 ml) of saline (Sigma) was injected at thecannulation and visualized by angiography (FIG. 5a ) as a control.

This example demonstrates visualization of the thixotropic turbid gelmaterial using angiography.

Example 9

This Example describes preparation of a thixotropic, turbid gel materialthat contains a first bioactive agent capable of treating vasculartissue in sufficient amounts to treat a vascular condition and a secondbioactive agent in the form of a phase contrast agent to assistangiographic visualization of the gel material. This exampledemonstrates visualization of the gel material using angiography.

A first solution (referred herein as Solution 9A) was prepared by mixingPBS with 0.40 g/ml hydroxypropyl-β-cyclodextrin (HPβCD) (Sigma-Aldrich,St. Louis, Mo.) and 0.20 g/ml alpha-cyclodextrin (αCD) (Sigma-Aldrich,St. Louis, Mo.) through stirring and heating (60° C.), followed byadding dexamethasone at 20 mg/ml and 600 mg/ml of iopamidol (Hovione,Loures, Portugal) with stirring and heating (60° C.). Solution 9A didnot form a gel material and was not turbid.

A second solution (referred herein as Solution 9B) was prepared bydissolving PEG of average Mn=8kDa (0.26 g/ml) with PBS. Solution 9B didnot form a gel material and was not turbid.

Equal volumes of Solution 9A and Solution 9B were combined with mixingto form Gel Material E. Gel Material E was turbid, and was opaque andwhite in appearance.

A healthy canine was anaesthetized. A segment of canine jugular vein,approximately five centimeters (5 cm) in length, was surgically exposed.Blood flow in the segment was stopped by constriction of the vein withclamps positioned at the proximal and distal ends of the segment. Avascular tissue treatment site was the length of vessel between theclamps. The vascular treatment site was cannulated. Blood within thevessel lumen was withdrawn at the cannulation using a syringe. One tothree milliliters (3 to 4 ml) of Gel Material E was injected at thecannulation and visualized by angiography (FIG. 5d ).

After angiography, the clamps were removed from the blood vesselsegment, and blood flow was permitted to resume in the vasculartreatment site for approximately five minutes (5 min). Then, blood flowin the segment was again stopped by constriction of the vein with clampspositioned at the proximal and distal ends of the segment. A vasculartissue treatment site was the length of vessel between the clamps. Thevascular treatment site was cannulated. Blood within the vessel lumenwas withdrawn at the cannulation using a syringe. One to threemilliliters (3 to 4 ml) of Gel Material A (as described in Example 1,supra, and which contained no phase contrast agent) was injected at thecannulation and visualized by angiography (FIG. 5b ) as a control.

After angiography, the clamps were removed from the blood vesselsegment, and blood flow was permitted to resume in the vasculartreatment site for approximately five minutes (5 min). Then, blood flowin the segment was again stopped by constriction of the vein with clampspositioned at the proximal and distal ends of the segment. A vasculartissue treatment site was the length of vessel between the clamps. Thevascular treatment site was cannulated. Blood within the vessel lumenwas withdrawn at the cannulation using a syringe. One to threemilliliters (3 to 4 ml) of saline (Sigma) was injected at thecannulation and visualized by angiography (FIG. 5a ) as a control.

This example demonstrates visualization of the thixotropic turbid gelmaterial using angiography.

Example 10

This Example describes delivery through a medical device of athixotropic, turbid gel material containing a bioactive agent capable oftreating vascular tissue in sufficient amounts to inhibit a vascularcondition.

Gel Material A (as described in Example 1, supra) was injected throughthree different medical devices under hand compression of a syringeattached to each medical device: a 4 French catheter (100 cm in length)(Cordis, Warren, N.J.); a 6 French catheter (90 cm in length) (Cordis);and a 20 Gauge needle (2.54 cm in length) (Monoject, Mansfield, Mass.).The medical device was attached to a five milliliter (5 ml) luer locksyringe (Becton Dickinson, Franklin Lakes, N.J.). Gel Material A passedthrough all three medical devices with hand compression of the attachedsyringe. This example demonstrates the method of administering the gelmaterial by injection through a needle. This example also demonstratesthe method of administering the gel material by endovascular deliveryvia a catheter.

Example 11

This Example describes in vivo delivery of dexamethasone to arterialtissue (“treated vascular tissue”) according to a method of the presentinvention.

A thixotropic, turbid gel material (herein referred to as Gel Material11A) was made by the following steps.

A first solution (referred herein as Solution 11A) was prepared bymixing phosphate buffered saline (PBS) (0.15M NaCl, pH 7.4, InvitrogenCorporation Carlsbad, Calif.) with 0.57 g/mlhydroxypropyl-β-cyclodextrin (HPβCD) (Sigma-Aldrich, St. Louis, Mo.) and0.20 g/ml alpha-cyclodextrin (αCD) (Sigma-Aldrich) through stirring andheating (60° C.). Solution 11A did not form a gel material and was notturbid.

Then, a dexamethasone mixture was made by combining tritium-labeleddexamethasone (Perkin Elmer, Waltham, Massachusetts Perkin Elmer) andunlabeled dexamethasone (Pharmacia & Upjohn Company) at a ratio ofapproximately 9 μg/g. Solution 11B was formed by solubilizingapproximately 20 mg/ml of the dexamethasone mixture in Solution 11A.Solution 11B did not form a gel material and was not turbid.

Solution 11C was prepared by dissolving polyethylene glycol (PEG, DowChemical, Midland, Mich.) of average Mn=8 kDa (0.26 g/ml) with PBS.Solution 11C did not form a gel material and was not turbid.

Equal volumes of Solution 11B and Solution 11C were combined with mixingto form Gel Material 11A. Gel Material 11A was turbid, and was opaqueand white in appearance.

Healthy canines were anaesthetized. A five centimeter (5 cm) segment ofcanine femoral artery was surgically exposed. Blood flow in the segmentwas stopped by constriction of the artery with rubber ties positioned atthe proximal and distal ends of the segment. A vascular tissue treatmentsite was the length of vessel between the rubber ties. The vasculartreatment site was cannulated. Blood within the vessel lumen waswithdrawn at the cannulation using a syringe. The lumen of the vasculartreatment site was irrigated three times with saline applied with asyringe at the cannulation. One to three milliliters (1 to 3 ml) of GelMaterial 11A was injected at the cannulation and allowed to contact theblood vessel lumen for a treatment period of two (2) minutes. No leakageof the Gel Material 11A from any treated vessel segment was observedduring the treatment period.

After the designated treatment period, the ties were removed from eachblood vessel segment, and blood flow was permitted to resume in thevascular treatment site for one hour (1 hr). Canine arteries arerelatively transparent, enabling observation with the unaided eye of GelMaterial 11A administration and removal from the vascular treatmentsite. Upon re-establishment of blood flow in the vascular treatmentsite, Gel Material 11A was observed to substantially dissolve withinapproximately one minute (1 min).

After approximately one hour (1hr) of blood flow, post-injectioncontrast angiography was performed to demonstrate the patency ofcapillaries and other vascular structures located distal to thetreatment site after Gel Material 11A dissolution in the blood stream.Angiography of arteries distal to the treatment site demonstrated normalblood perfusion after gel material dissolution in the blood stream.These results demonstrate that the method of administering the gelmaterial did not occlude vascular structures upon introduction intoflowing blood.

Following angiography, the vascular treatment site was harvested andwashed thoroughly with saline. Tissue sections (approximately 1 cm inlength) were taken from each vascular treatment site and digestedovernight in five milliliters (5 ml) of Solvable digestion fluid (PerkinElmer). Fifteen milliliters (15 ml) of HiSafe 2 (Perkin Elmer), ascintillation cocktail, was added to the tissue sections to permitscintillation counting and quantification of beta radiation emitted bythe tritium-labeled dexamethasone within each specimen.

A second group of healthy canines was anaesthetised. Control arterysections (approximately 1 cm in length) were obtained from thesecanines. The control artery sections were digested overnight in 5 ml ofSolvable digestion fluid (Perkin Elmer). Known amounts oftritium-labeled dexamethasone were added to the digestion fluid. Fifteenmilliliters (15 ml) of HiSafe 2 (Perkin Elmer), was added to the controlartery sections to permit scintillation counting and quantification ofthe beta-radiation emitted by the tritium-labeled dexamethasone withineach control artery section.

A scintillation counter (Perkin Elmer) was used to measure the betaradiation (disintegrations per minute) emitted by each control arterysection and to generate a linear standard curve of disintegrations perminute as a function of the tritium-labeled dexamethasone within eachsection. Radiation levels (disintegrations per minute) from the tissuesection were then compared to the standard curve to calculatetritium-labeled dexamethasone retained in the tissue section. The totalamount of dexamethasone retained in each tissue section was determinedby correlation of the total amount of dexamethasone in Gel Material 11Ato the measured amount of tritium-labeled dexamethasone in eachexperimental tissue section.

When Gel Material 11A containing dexamethasone was allowed to contact ablood vessel lumen devoid of blood for two minutes (2 min), an averageof 9.1 μg dexamethasone/g tissue was retained in each tissue sectionafter one hour (1 h) blood flow. The vascular treatment site includedthe tissue sections. Therefore, an average of 9.1 μg dexamethasone/gtissue was retained in the vascular treatment site at one hour (1 h).

Example 12

This Example describes preparation of a thixotropic, turbid gel materialthat contains a bioactive agent capable of treating vascular tissue insufficient amounts to treat a vascular condition.

A thixotropic, turbid gel material (herein referred to as Gel MaterialF) made from polyvinyl alcohol (PVA, Spectrum, Gardena, Calif.), sodiumborate (Borax, Sigma), polyoxyethylene sorbitol ester (Tween®20, Sigma),and dexamethasone (Pharmacia & Upjohn Company) was made by the followingsteps.

Three solutions were separately formed:

Solution 12A: 0.03 g PVA per milliliter water

Solution 12B: 10 mg dexamethasone per milliliter polyoxyethylenesorbitol ester

Solution 12C: 10 mg borax per milliliter water

Then, 0.5 ml of Solution 12B was thoroughly mixed with 9.5 ml Solution12A to form Solution 12D. Next, 0.5 ml of Solution 12C was added to 5 mlof Solution D. Upon mixing, a Gel Material F was formed and was turbid.

Example 13

This Example describes preparation of a thixotropic, turbid gel materialthat contains a bioactive agent capable of treating vascular tissue insufficient amounts to treat a vascular condition.

A thixotropic, turbid gel material (herein referred to as Gel MaterialG) made from polyvinyl alcohol (PVA, Spectrum, Gardena, Calif.) andsodium borate (Borax, Sigma), and HPβCD (Sigma), and dexamethasone(Pharmacia & Upjohn Company) was made by the following steps.

Three solutions were separately formed:

Solution 13A: 0.05 g PVA per milliliter water

Solution 13B: 0.20 g HPβCD per milliliter

Solution 13C: 10 mg borax per milliliter water

Then, Solution 13D was formed by solubilizing approximately 12 mgdexamethasone per milliliter in Solution 13B. Next, 2.5 ml Solution 13A,2.5 ml Solution 13D, and 0.25 ml Solution 13C were thoroughly combined.Upon mixing, a Gel Material G was formed and was turbid.

Example 14

This Example describes in vivo delivery of dexamethasone to venoustissue (“treated vascular tissue”) according to a method of the presentinvention using Gel Material Gas described in Example 13.

Healthy canines were anaesthetized. A five centimeter (5 cm) segment ofcanine jugular vein was surgically exposed. Blood flow in the segmentwas stopped by constriction of the vein with rubber ties positioned atthe proximal and distal ends of the segment. A vascular tissue treatmentsite was the length of vessel between the rubber ties. The vasculartreatment site was cannulated. Blood within the vessel lumen waswithdrawn at the cannulation using a syringe. The lumen of the vasculartreatment site was irrigated three times with saline applied with asyringe at the cannulation. One to three milliliters (3 to 4 ml) of GelMaterial G was injected at the cannulation and allowed to contact theblood vessel lumen for a treatment period of forty (40) minutes. Noleakage of the Gel Material G from any treated vessel segment wasobserved during the treatment period.

After the designated treatment period, the ties were removed from eachblood vessel segment, and blood flow was permitted to resume in thevascular treatment site for one hour (1 hr). Canine veins are relativelytransparent, enabling observation with the unaided eye of Gel Material Gadministration and removal from the vascular treatment site. Uponre-establishment of blood flow in the vascular treatment site, GelMaterial G was observed to substantially dissolve within approximatelyone minute (1 min). After one hour (1 hr) of blood flow, the vasculartreatment site was harvested and washed thoroughly with saline.

Tissue sections (approximately 1 cm in length) were taken from eachvascular treatment site. A histological examination of these sectionsrevealed a normal appearance of these sections. Three additionalsections of the vascular treatment site were analyzed for dexamethasonecontent by tissue extraction and quantified with high performance liquidchromatography combined with dual mass spectroscopy. Dexamethasonelevels in these tissue sections were approximately 15.9±9.8 μg per gramtissue, demonstrating that the method of the present invention deliversa bioactive agent to a vascular tissue treatment site.

Example 15

This Example describes the preparation of a thixotropic, turbid gelmaterial that contains a bioactive agent capable of treating vasculartissue in sufficient amounts to treat a vascular condition.

A thixotropic, turbid gel material (herein referred to as Gel MaterialH) made from sodium alginate (Sigma), calcium chloride (Sigma),hydroxypropyl-β-cyclodextrin (HPβCD) (Sigma), and dexamethasone(Pharmacia & Upjohn Company) was made by the following steps.

Three solutions were separately formed:

Solution 15A: 1.7 mg calcium chloride per milliliter water

Solution 15B: 0.40 g HPβCD per milliliter water

Solution 15C: 20 mg sodium alginate per milliliter water

Then, Solution 15D was formed by solubilizing approximately 20 mgdexamethasone per milliliter of Solution 15B. Next, 2.5 ml Solution 15A,2.5 ml Solution 15D, and 2.5 m I Solution 15C were combined. Uponmixing, a Gel Material H was formed and was turbid.

Example 16

This Example describes the preparation of a thixotropic, turbid gelmaterial that contains a bioactive agent capable of treating vasculartissue in sufficient amounts to treat a vascular condition.

A thixotropic, turbid gel material (herein referred to as Gel MaterialX) made from dextran (Mn=4kDa, Sigma) and potassium chloride (Sigma) andhydroxypropyl-β-cyclodextrin (HPβCD) (Sigma), and dexamethasone(Pharmacia & Upjohn Company) is made by the following steps.

Two solutions are separately formed:

Solution 16A: 0.40 g HPβCD per ml water

Solution 16B: 0.22 g potassium chloride per g water

Then, Solution 16C is formed by solubilizing 10 mg/ml dexamethasone inSolution 16A. Next, 0.5 g dextran is solubilized by 0.5 ml of Solution16C. Finally, 0.5 ml Solution 16B is added. Upon mixing, Gel Material Xis formed and was turbid.

Example 17

This Example describes characterization of a thixotropic, turbid gelmaterial that contains a bioactive agent capable of treating vasculartissue in sufficient amounts to treat a vascular condition. Thixotropyof Gel Material A was demonstrated by rheometry.

The viscosity of Gel Material A was characterized over a range of shearrates using a rheometer (Model AR-G2, TA Instruments, New Castle, Del.).This analysis technique involved measurement of shear stress duringshear rate “ramp up” and subsequent “ramp down.” Samples were analyzedat 25° C. with a forty millimeter (40 mm) cone and plate geometry. Aboutone milliliter (1 ml) of Gel Material A was injected from a needle-lesssyringe onto the plate and allowed to equilibrate for 3 minutes. Then, ashear “ramp up” step was performed, whereby the shear rate was increasedfrom 0.1 to 1.0 s⁻¹ over two minutes (2 min). Subsequently, a “rampdown” step was performed, whereby the shear rate was decreased from 1.0to 0.1 s⁻¹ over two minutes (2 min).

Apparent viscosity at each point was calculated as the ratio of shearstress to shear rate. Initial viscosity at 0.1 s⁻¹ was approximately 90Pa·s. The viscosity of Gel Material A was observed to decrease withincreasing shear (during the shear “ramp up”). At 1.0 s⁻¹, the viscosityof Gel Material A was approximately 17 Pa·s. As the shear rate was thendecreased (the “ramp down” step), the viscosity of Gel Material A wasseen to increase. At the conclusion of the ramp down step, the viscosityof Gel Material A at 0.1 s⁻¹ was approximately 55 Pa·s.

Example 18

This Example describes an implantable medical device having athixotropic, turbid, gel material containing a bioactive agent capableof treating vascular tissue in sufficient amounts to treat a vascularcondition applied to at least a portion of the implantable medicaldevice.

The implantable medical device used in this example was in the form of anitinol wire reinforced tube made of a porous, expanded,polytetrafluoroethylene (ePTFE) material obtained from W.L. Gore &Associates, Inc., Flagstaff, Ariz. under the tradename VIABAHN®Endoprosthesis. The tubular device was fifteen centimeters (15 cm) inlength and six millimeters (6 mm) in diameter.

Gel Material A (described in Example 1, supra) was applied to anexterior surface of the implantable medical device using aneedle-containing syringe. Once applied, the gel material was seen toadhere to the exterior surface of the implantable medical device.

The implantable medical device was mechanically expanded. Uponexpansion, the implantable medical device expanded from a first diameterand a first surface area to a second diameter and a second surface area.A substantial portion of Gel Material A applied to the exterior surfaceof the implantable medical device was seen to remain adherent to theexterior surface of the implantable medical device during expansion ofthe implantable medical device.

Example 19

This Example describes an implantable medical device having athixotropic, turbid, gel material containing a bioactive agent capableof treating vascular tissue in sufficient amounts to treat a vascularcondition applied to at least a portion of the implantable medicaldevice.

The implantable medical device used in this example was in the form of acatheter-based device. The catheter-based device was in the form of anendovascular angioplasty balloon (POWERFLEX® P3, Cat. No. 420-4040L,Cordis Corporation). The restraining sheath of the balloon was removedfrom the implantable medical device. Then, Gel Material A (described inExample 1, supra) was applied to an exterior surface of the balloon ofthe implantable medical device using a needle-containing syringe. Onceapplied, the gel material was seen to adhere to the exterior surface ofthe balloon.

The balloon was mechanically expanded according to instructions for useprovided with the packaging. Upon mechanical expansion, the balloonexpanded from a first diameter and a first surface area to a seconddiameter and a second surface area. A substantial portion of GelMaterial A applied to the exterior surface of the implantable medicaldevice was seen to remain adherent to the exterior surface of theimplantable medical device during and after mechanical expansion of theimplantable medical device.

What is claimed is:
 1. A catheter-based implantable medical vascular device having a first diameter and a first surface area, and expandable to a second diameter and a second surface area within a vascular structure, in use; the device comprising at least one thixotropic, turbid, hydrogel material applied to at least a portion of said medical device, wherein the hydrogel material is applied to a surface of the device to create an applicated device of the first diameter and the first surface area; the hydrogel material comprising cyclodextrin, an aqueous solvent component and a polymer chain component, and at least one bioactive agent capable of treating vascular tissue upon release of said bioactive agent from said hydrogel material.
 2. The catheter-based implantable medical vascular device as claimed in claim 1, the hydrogel material comprising a pharmacologically effective amount of the at least one bioactive agent, wherein the polymer chain component comprises ethylene glycol units that form the hydrogel with the cyclodextrin, wherein the cyclodextrin and the polymer chain unit self-assemble to form the hydrogel by spontaneous association and are present in the composition in respective amounts effective to make the hydrogel thixotropic.
 3. The catheter-based implantable medical vascular device of claim 1 wherein catheter-based implantable medical vascular device is a nitinol wire reinforced expanded polytetrafluoroethylene-based vascular prosthesis.
 4. The catheter-based implantable medical vascular device of claim 1 wherein catheter-based implantable medical vascular device is an endovascular angioplasty balloon.
 5. The catheter-based implantable medical vascular device of claim 1, further comprising a surface having the hydrogel material impregnated therein.
 6. The catheter-based implantable medical vascular device of claim 1, wherein the polymer chain component comprises polyethers such as polyethylene glycol, polypropylene glycol, poly(ethylene glycol-co-propylene glycol), copolymers of polyethylene glycol, and copolymers of polypropylene glycol; polyols such as polyvinyl alcohol and polyallyl alcohol; polyanions such as polyacrylic acid and poly(methacrylic acid); polyanionic polysaccharides such as alginate, heparin, heparin sulfate, dextran sulfate, xanthan, carrageenan, gum arabic, tragacanth, arabinogalactan, and pectin; neutral polysaccharides such as agar, agarose, hyaluronic acid, carboxymethylcellulose, and dextran; macrocyclic polysaccharides such as cyclodextrin and hydroxypropyl cyclodextrin; polycations such as poly(lysine), poly(allylamine), poly(ethyleneimine), poly(guanidine), polyvinylamine), α,ω-polyethyleneglycol-diamine, and poly(quaternary amine); polyanionic polysaccharides such as chitin and chitosan; polyacrylonitriles such as hydrolyzed polyacrylonitrile, poly(acrylamide-co-acrylonitrile), and their copolymers; and/or protein based polymers such as gelatin, collagen, thrombin, and fibrin.
 7. The catheter-based implantable medical vascular device according to claim 1, wherein the hydrogel material comprises α-cyclodextrin (αCD) and polyethylene glycol (PEG).
 8. The catheter-based implantable medical vascular device according to claim 1, wherein the hydrogel material comprises polyethylene glycol, α-cyclodextrin (αCD), and hydroxypropyl-β-cyclodextrin (HPβCD).
 9. The catheter-based implantable medical vascular device according to claim 1, wherein the hydrogel material comprises polyvinyl alcohol, sodium borate, and polyoxyethylene sorbitol ester.
 10. The catheter-based implantable medical vascular device according to claim 1, wherein the hydrogel material comprises sodium alginate, calcium chloride, and hydroxypropyl-β-cyclodextrin (HPβCD).
 11. The catheter-based implantable medical vascular device according to claim 1, wherein the hydrogel material comprises dextran, potassium chloride, and hydroxypropyl-β-cyclodextrin (HPβCD). 